Immune System: The Fates of Individual T Cells

03/21/2013

By charting the differing fates of individual T cells, researchers have shown that previously unpredictable aspects of the adaptive immune response can be effectively modeled.

The crucial question: What determines which of the immune system's millions of cells will mobilize to fight an acute infection and which will be held back to survive long-term, forming the basis of the immunological memory? The scientists' findings could have implications for improved immunotherapy and vaccination strategies.

The scientists found that the immediate immune response to an infection or tumor is mounted by a relatively tiny fraction of the so-called CD8+ T cells that are capable of recognizing the associated antigen. These few rapidly expand into giant populations of short-lived T cells targeted at killing infected cells or cancer cells. Meanwhile the vast majority remain in smaller populations geared toward longevity, to help ensure that the immune system will remember the antigen when it appears again in the future. "Up to now, it was only possible to observe groups of immune cells during the response to an infection," says Professor Dirk Busch of the Technische Universitaet Muenchen (TUM). "We have developed technology that enables us to observe individual T cells."

Researchers at TUM introduced specially marked T cells into mice and then triggered a specific immune reaction. Around seven days later, they were able to determine how many descendant cells, and what kinds, had been generated by individual T cells. Biomathematical modeling, using an approach co-developed with the group of Professor Thomas Hoefer at Heidelberg, helped to explain what the data showed. "One cannot predict which 'career paths' the descendants of an individual killer T cell will take," says first author Veit Buchholz from TUM. “This is a matter of chance, like a single roll of the dice. To generate a predictable immune response, we have found that a sample of at least 50 individual cells is needed."

From analysis of many of the huge populations of short-lived killer cells and the relatively tiny populations of long-lived memory cells, the researchers were able to reconstruct the T cells' development program and predict their behavior: All of the cells proceed along the same path of development, but they do not go the same distance. That is, the few cells that generate giant populations of short-lived infection fighters have gone through the same stage as those fated to produce memory cells – but they have left that stage behind to provide immediate protection.

There are several ways these findings could become important in the setting of human health, the researchers explain – in improving the effectiveness of immunotherapy against cancer, for example, or in optimizing treatment for older people, who tend to have significantly fewer copies of a given type of immune cell. "The future memory cell stands at the beginning of an expansion process with two extreme forms of differentiation," Buchholz says, "and ideally there should be a balance, so that the memory pool is not depleted. So we can think about how to tweak vaccination schemes to first allow expansion and not let differentiation kick in too early."